Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: SciPharm Sàrl, 7, Fausermillen, L-6689, Mertert, Luxembourg
Pharmacotherapeutic group: Antithrombotic agents, platelet aggregation inhibitors excl. heparin
ATC code: B01AC21
Treprostinil is a prostacyclin analogue. It exerts a direct vasodilation effect on the pulmonary and systemic arterial circulation and, inhibits platelet aggregation.
In a randomised, multi-centre, controlled clinical trial, a total of 105 male (53.3%) and female (46.7%) adult patients with inoperable CTEPH or persistent or recurrent CTEPH after pulmonary endarterectomy (18-88 years of age, mean 64 years) were treated. Patients were required to have CTEPH classified as severe, as defined by an un-encouraged six-minute walk test (6MWT) of between 150 and 400 meters and a classification in the WHO/NYHA functional class III or IV. Patients were divided into two treprostinil treatment groups (53 high dose and 52 low dose patients, treated with subcutaneous infusion for a total of 24 weeks) as follows. In the high dose group, patients were administered a subcutaneous dose via infusion pump that increased from approximately 1 to a target dose of approximately 30 ng/kg/min for the first 12 weeks, followed by 12 weeks of stable perfusion; in the low dose group, the target dose was approximately 3 ng/kg/min following the same schedule.
The primary efficacy analysis was based on the individual difference between the 6MWT data at baseline and after 24 weeks. Treprostinil improved the six-minute walk distance (6MWT, six-minute walk test: baseline vs. 24 weeks of treatment) by a mean of 45.43 m in the high dose group versus 3.83 m in the low dose group (p<0.05, ANCOVA). Exploratory secondary efficacy (low vs. high) measures, after 24 weeks of treatment, showed -significant improvements in New York Heart Association functional (NYHA) class, haemodynamic parameters (mean pulmonary vascular resistance, mean pulmonary arterial pressure, mean cardiac output, and mean cardiac index) and median pro-BNP (brain natriuretic peptide values) in favor of the high dose group. No significant differences between the two test groups in the number of patients showing a “clinical worsening”, defined as a reduction of 6MWD of 20% compared to baseline, worsening of NYHA functional class and/or hospitalisation due to CTEPH with the need of additional pulmonary hypertension specific treatment, were observed. High dose treprostinil showed no significant changes in the Borg Dyspnoea Score (measured during the 6MWT), or the summed Quality of Life score as assessed by the Minnesota Living with Heart Failure Questionnaire.
In humans, steady-state plasma concentrations are usually achieved within 15 to 18 hours of the initiation of either subcutaneous or intravenous infusion of treprostinil. Steady-state plasma concentrations of treprostinil are dose-proportional at infusion rates of 2.5 up to 125 ng/kg/min.
The mean apparent elimination half-life following subcutaneous administration ranged from 1.32 to 1.42 hours after infusions over 6 hours, 4.61 hours after infusions over 72 hours, and 2.93 hours after infusions lasting at least three weeks. The mean volume of distribution for treprostinil ranged from 1.11 to 1.22 l/kg, and plasma clearance ranged from 586.2 to 646.9 ml/kg/h. Clearance is lower in obese subjects (BMI >30 kg/m²).
In a seven-day chronic pharmacokinetic study in 14 healthy volunteers with treprostinil doses ranging from 2.5 to 15 ng/kg/min administered by subcutaneous infusion, steady state plasma treprostinil concentrations reached peak levels twice (at 1 a.m. and 10 a.m. respectively) and trough levels twice (at 7 a.m. and 4 p.m. respectively). The peak concentrations were approximately 20% to 30% higher than the trough concentrations.
In a study conducted on healthy volunteers using [14C] radioactive treprostinil, 78.6% and 13.4% of the subcutaneous radioactive dose were recovered in the urine and faeces respectively over a period of 224 hours. No single major metabolite was observed. Five metabolites were detected in the urine, ranging from 10.2% to 15.5% of the dose administered. These five metabolites accounted for a combined total of 64.4%. Three are products of oxidation of the 3-hydroxyloctyl side chain, one is a glucuroconjugated derivative (treprostinil glucuronide) and one is unidentified. Only 3.7% of the dose was recovered in the urine as unchanged parent drug.
An in vitro study demonstrated no inhibitory potential of treprostinil to human hepatic microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A).
Moreover, administration of treprostinil had no inducing effect on hepatic microsomal protein, total cytochrome (CYP) P 450 content or on the activities of the isoenzymes CYP1A, CYP2B and CYP3A.
In patients with portopulmonary hypertension and mild (n=4) or moderate (n=5) hepatic insufficiency, treprostinil at a subcutaneous dose of 10 ng/kg/min for 150 minutes had an AUC0-24h that was increased 260% and 510%, respectively, compared to healthy subjects. Clearance in patients with hepatic insufficiency was reduced by up to 80% compared to healthy adults (see section 4.2).
In a multivariate analysis of pooled studies, patients in the age group ≥65 years had a small reduction in plasma clearance of treprostinil. However, most publications regarded either healthy volunteers or patient with PAH. CTEPH patients were rarely described. Age stratification was not performed in any publication. As only few studies reported on PK parameters but none reported both on CTEPH indication and PK data, no information is available on the pharmacokinetics of treprostinil in elderly patients.
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and toxicity to reproduction.
In 13 and 26 week studies continuous subcutaneous infusions of treprostinil sodium caused infusion site reactions in rats and dogs (oedema/erythema, masses/swellings, pain/sensitivity to touch). In dogs severe clinical effects (hypoactivity, emesis, loose stool and infusion site oedema) and death (associated with intestinal intussusceptions and rectal prolapse) were observed in animals administered ≥300ng/kg/min. Mean steady state plasma treprostinil levels of 7.85ng/ml were measured in these animals. Plasma levels of this order may be achieved in humans treated with treprostinil infusions at >50ng/kg/min.
As a continuously sufficient exposure to treprostinil has not been proven for any dosage tested in the reproductive studies in rats, these studies might be insufficient regarding possible effects on fertility, prenatal and postnatal development.
No long-term animal studies have been performed to evaluate treprostinil’s carcinogenic potential.
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